Arecurring theme in the previous articles in this series has been the challenges posed to hunters of novel drugs by conflicting experimental and clinical observations as well as controversy over competing scientific hypotheses. The story of the discovery of ß-hydroxy-ß-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors illustrates yet again the pivotal importance of academic/industrial collaboration in cardiovascular drug discovery. 1-3 There are three interwoven themes in this article, which are: (i) mechanisms of cholesterol homeostasis; (ii) controversies over hyperlipidemia/ hypercholesterolemia and atherosclerosis; and (iii) the discovery of a first HMG-CoA reductase inhibitor...